Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.7 (plasmin)
 9,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Plasminogen activator converts plasminogen to plasmin, and plasmin activates the latent matrix metalloproteinases. Tissue plasminogen activator (t-PA) is one of the important proteolysis factors present in human inflamed tissues. However, few studies reported on the mechanisms of tissue destruction via a t-PA proteolysis pathway in pulpal and periapical diseases. The subsequent reactions leading to pulpal and periapical injury after the induction of proinflammatory cytokines remains to be elucidated. The aim of this study was to investigate the effects of interleukin-1alpha and tumor necrosis factor-alpha on the expression of t-PA mRNA gene in cultured human pulp and gingival fibroblasts. The mRNAs for t-PA were measured by reverse transcription-polymerase chain reaction at 2, 6, and 24 h. The results show that both cytokines induced significantly high levels of t-PA mRNA gene expression in human pulp fibroblasts. The peak of t-PA mRNA levels induced by both proinflammatory cytokines was at the 6-h incubation period. Interleukin-1alpha was found to be more effective in induction of t-PA gene expression than tumor necrosis factor-alpha. In addition, a similar induction pattern was also found in human gingival fibroblasts. These results indicate that proinflammatory cytokines can induce t-PA gene expression and such an effect may partially contribute to the destruction of pulpal and periapical tissues through dysregulated pericellular proteolysis. An understanding of the mechanism could not only further define the role of immune events in pulpal and periapical diseases but also have important implication for pharmacological intervention.
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PMID:Induction of tissue plasminogen activator gene expression by proinflammatory cytokines in human pulp and gingival fibroblasts. 1259 10

Tissue plasminogen activator (tPA) is a serine protease that converts plasminogen to plasmin. It plays an important role in the nervous system, including the processes of neuronal migration, neurite outgrowth, and neuronal plasticity. tPA has also been suggested to have a role in several neuropathological conditions, such as cerebral ischemia, seizures, and demyelinating diseases. To investigate the role of tPA in spinal cord injury, wild-type mice and mice with homozygous tPA deficiency (tPA(-/-) mice) were subjected to spinal cord contusion and the differences of hindlimb function, electrophysiological changes, and histopathological changes were assessed for 6 weeks. Functional recovery was greater in tPA(-/-) mice than in wild-type mice throughout the observation period. The time course of myoelectric motor-evoked potentials supported the hindlimb functional findings. Histological examination showed that injured areas were smaller in tPA(-/-) mice than wild-type mice on Luxol fast blue staining or myelin basic protein and neurofilament protein immunostaining at 6 weeks after contusion. Electron microscopy showed that the white matter was better preserved in tPA(-/-) mice than in wild-type mice. The expression of tPA protein was widespread on the first day after contusion and this expression was detected for at least a week. Activation of microglia/macrophages and apoptotic cell death were significantly reduced in tPA(-/-) mice after contusion. This study shows that neural damage is decreased in tPA(-/-) mice after spinal cord injury. Suppression of tPA production may help to decrease secondary injury after spinal cord contusion.
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PMID:Decreased neural damage after spinal cord injury in tPA-deficient mice. 1261 87

Tissue plasminogen activator (tPA), a neuronal as well as the key fibrinolytic enzyme, is found concentrated on demyelinated axons in multiple sclerosis lesions together with fibrin(ogen) deposits. The decreased tPA activity in normal-appearing white and grey matter and lesions of multiple sclerosis is reflected in diminished fibrinolysis as measured by a clot lysis assay. Nonetheless, peptide products of fibrin, including D-dimer, accumulate on demyelinated axons-the result of fibrinogen entry through a compromised blood-brain barrier (BBB). Analysis of tissue samples on reducing and non-reducing polyacrylamide gels demonstrates complexes of tPA with plasminogen activator inhibitor-1 (PAI-1) but not with neuroserpin, a tPA-specific inhibitor concentrated in grey matter. As total tPA protein remains unchanged in acute lesions and the concentration of PAI-1 rises several fold, complex formation is a probable cause of the impaired fibrinolysis. Although the tPA-plasmin cascade promotes neurodegeneration in excitotoxin-induced neuronal death, in inflammatory conditions with BBB disruption it has been demonstrated to have a protective role in removing fibrin, which exacerbates axonal injury. The impaired fibrinolytic capacity resulting from increased PAI-1 synthesis and complex formation with tPA, which is detectable prior to lesion formation, therefore has the potential to contribute to axonal damage in multiple sclerosis.
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PMID:Impaired fibrinolysis in multiple sclerosis: a role for tissue plasminogen activator inhibitors. 1280 24

Tissue plasminogen activator is a serine protease that plays the dominant role in removal of fibrin from the vascular tree by activating plasminogen to the primary fibrinolytic enzyme, plasmin. Tissue plasminogen activator has a widespread neuroendocrine distribution in addition to its expression by endothelial cells. Within neuroendocrine cells, secretory proteins are sorted into one of two pathways: regulated or constitutive. Proteins entering the regulated pathway are concentrated and stored in vesicles, and subsequently released upon stimulation by a secretagogue. In contrast, in the constitutive pathway, newly synthesized protein is not stored but is transported directly to the cell surface and secreted even in the absence of an extracellular signal. The focus of this article is to review recent studies demonstrating that tissue plasminogen activator is targeted to the regulated secretory pathway in neuroendocrine cells and to discuss the physiological implications of the trafficking of tissue plasminogen activator to regulated secretory vesicles.
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PMID:Targeting of tissue plasminogen activator to the regulated pathway of secretion. 1498 55

Tissue plasminogen activator (tPA) is a serine protease that catalyzes the conversion of plasminogen (plg) to plasmin, which in turn functions to degrade extracellular matrix proteins in the central nervous system. The tPA-plasmin system plays a role in synaptic plasticity and remodeling. Here we show that this protease system participates in the rewarding effects of morphine by acutely regulating morphine-induced dopamine release in the nucleus accumbens (NAcc). A single morphine treatment induced tPA mRNA and protein expression in a naloxone-sensitive manner, which was associated with an increase in the enzyme activity in the NAcc. The acute effect of morphine in inducing tPA expression was diminished after repeated administration. Morphine-induced conditioned place preference and hyperlocomotion were significantly reduced in tPA(-/-) and plg(-/-) mice, being accompanied by a loss of morphine-induced dopamine release in the NAcc. The defect of morphine-induced dopamine release and hyperlocomotion in tPA(-/-) mice was reversed by microinjections of either exogenous tPA or plasmin into the NAcc. Our findings demonstrate a previously undescribed function of the tPA-plasmin system in regulating dopamine release, which is involved in the rewarding effects of morphine.
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PMID:The tissue plasminogen activator-plasmin system participates in the rewarding effect of morphine by regulating dopamine release. 1498 9

Tissue plasminogen activator (tPA), a fibrin specific activator for the conversion of plasminogen to plasmin, stimulates thrombolysis and rescues ischemic brain by restoring blood flow. However, emerging data suggests that under some conditions, both tPA and plasmin, which are broad spectrum protease enzymes, are potentially neurotoxic if they reach the extracellular space. Animal models suggest that in severe ischemia with injury to the blood brain barrier (BBB) there is injury attributed to the protease effects of this exogenous tPA. Besides clot lysis per se, tPA may have pleiotropic actions in the brain, including direct vasoactivity, cleaveage of the N-methyl-D-aspartate (NMDA) NR1 subunit, amplification of intracellular Ca++ conductance, and activation of other extracellular proteases from the matrix metalloproteinase (MMP) family, e.g. MMP-9. These effects may increase excitotoxicity, further damage the BBB, and worsen edema and cerebral hemorrhage. If tPA is effective and reverses ischemia promptly, the BBB remains intact and exogenous tPA remains within the vascular space. If tPA is ineffective and ischemia is prolonged, there is the risk that exogenous tPA will injure both the neurovascular unit and the brain. Methods of neuroprotection, which prevent tPA toxicity or additional mechanical means to open cerebral vessels, are now needed.
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PMID:The neurotoxicity of tissue plasminogen activator? 1535 16

Tissue plasminogen activator (tPA) is a serine protease involved in the degradation of blood clots through the activation of plasminogen to plasmin. Here we report on the identification of tPA as a specific protease able to activate platelet-derived growth factor C (PDGF-C). The newly identified PDGF-C is secreted as a latent dimeric factor (PDGF-CC) that upon proteolytic removal of the N-terminal CUB domains becomes a PDGF receptor alpha agonist. The CUB domains in PDGF-CC directly interact with tPA, and fibroblasts from tPA-deficient mice fail to activate latent PDGF-CC. We further demonstrate that growth of primary fibroblasts in culture is dependent on a tPA-mediated cleavage of latent PDGF-CC, generating a growth stimulatory loop. Immunohistochemical analysis showed similar expression patterns of PDGF-C and tPA in developing mouse embryos and in tumors, indicating both autocrine and paracrine modes of activation of PDGF receptor-mediated signaling pathways. The identification of tPA as an activator of PDGF signaling establishes a novel role for the protease in normal and pathological tissue growth and maintenance, distinct from its well-known role in plasminogen activation and fibrinolysis.
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PMID:Tissue plasminogen activator is a potent activator of PDGF-CC. 1537 73

A novel enzyme drug delivery system, Antibody, Targeted, Triggered, Electrically, Modified, Prodrug, Type, Strategy ("ATTEMPTS"), was developed in our laboratory to attenuate the toxicity associated with drug activity at non-targeted tissues. Tissue plasminogen activator is a prime example of an enzyme drug that exhibits systemic toxicity due to its indiscriminate activation of both targeted (i.e., clot-bound) and non-targeted (i.e., systemic) plasminogen. In brief, tissue plasminogen activator (t-PA) was modified to contain positive surface charges and then rendered inactive upon electrostatic binding with a negatively charged heparin-antifibrin antibody conjugate. After targeting the complex to the clot site, t-PA activity was restored by administration of protamine, a clinical heparin antidote. Cation-modified t-PA (CM-tPA) was obtained by chemical conjugation of t-PA with a poly(Arg)7Cys peptide using the crosslinker N-succinimidyl 3-2-(pyridlydithio)propionate (SPDP). Anti-fibrin IgG was chemically conjugated with heparin via oxidation of the carbohydrate moiety on its Fc region. Both in vitro characterization and in vivo studies using a rat thrombosis model clearly demonstrated that heparin-IgG conjugate induced inhibition of CM-tPA could be effectively reversed upon addition of protamine. Overall, the ATTEMPTS system was proven to induce clot dissolution without causing t-PA associated systemic toxicity due to the degradation of critical plasma factors by systemic plasmin production.
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PMID:Application of "ATTEMPTS" for drug delivery. 1558 92

Tissue plasminogen activator (tPA) is the predominant plasminogen activator present in the vascular and nervous systems. Prior studies of the two have emphasized different tPA sources; respectively, endothelium and neurons. A closer relationship is now suggested by evidence that the peripheral sympathetic nervous system synthesizes and infuses enzymatically active tPA into small artery walls and the microcirculation. TPA may thus be the only known neural product able to effect degradation of the artery wall extracellular matrix. This brief review considers historical and current indications for the existence of such an autonomically controlled system and some physiologic implications. Immunohistochemical tPA expression in small arteries and arterioles is more prominent in the outer wall sympathetic axon plexus than in endothelium. Its presence in nerve filaments beneath the seldom-studied adventitia was obscured in earlier localizations. The systemic impact of a neural distribution is suggested by a 60% reduction of blood tPA activity after chemical sympathectomy. TPA-bearing axons extend outward from ganglion neuron cell bodies to reach even thin-walled vasa vasora and uveal microvessels. Ganglion cell bodies synthesize and package tPA in vesicles for the long axoplasmic transport. Densely innervated intact vessels release much greater amounts of tPA in vitro than do larger vessels, indicating a high neuron tPA production capacity and a large storage reservoir available within axon networks. The influence of an autonomically controlled plasmin production within small artery walls on regulation of blood pressure and capillary perfusion awaits further investigation. Its possible role in the pathogenesis of vessel wall matrix degradations in aging, hypertension, and diabetes may also merit further consideration.
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PMID:Distribution of sympathetic tissue plasminogen activator (tPA) to a distant microvasculature. 1567 11

Tissue plasminogen activator (tPA) is the main activator of plasminogen into plasmin in the brain where it may have beneficial roles but also neurotoxic effects that could be plasmin dependent or not. Little is known about the substrates and pathways that mediate plasmin-independent tPA neurotoxicity. Here we show in primary hippocampal neurons that tPA promotes a catalytic-independent activation of the extracellular regulated kinase (Erk)1/2 signal transduction pathway through the N-methyl-D-aspartate receptor, G-proteins and protein kinase C. This results in GSK3 activation in a process that requires de novo synthesis of proteins, and leads to tau aberrant phosphorylation, microtubule destabilization and apoptosis. Similar effects are produced by amyloid aggregates in a tPA-dependent manner, as demonstrated by pharmacological treatments and in wt and tPA-/- mice neurons. Consistently, in Alzheimer's disease (AD) patients' brains, high levels of tPA colocalize with amyloid-rich areas, activated Erk1/2 and phosphorylated tau. This is the first demonstration of an intracellular pathway by which tPA triggers kinase activation, tau phosphorylation and neurotoxicity, suggesting a key role for this molecule in AD pathology.
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PMID:Tissue plasminogen activator mediates amyloid-induced neurotoxicity via Erk1/2 activation. 1586 Nov 34


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